<p>Ischemic stroke and thrombotic vascular occlusion remain leading causes of mortality and disability worldwide, yet current therapies operate largely in an open-loop paradigm, delivering thrombolytics or mechanical intervention without adaptive feedback on clot state or treatment response. This review reframes thrombolysis as a dynamic, controllable biological process and introduces a systems-engineering perspective built around the Sense → Target → Lyse → Report framework for closed-loop nanomedicine. We synthesize advances across nanotechnology, thrombosis biology, and bioresponsive materials to examine how next-generation nanosystems can detect clot-specific biochemical and biomechanical cues, localize to thrombi under physiological flow, actuate controlled lytic activity, and provide real-time reporting of therapeutic progress. We first characterize the thrombus as a heterogeneous, evolving immunothrombotic structure. It comprises platelet-rich shells, red blood cell (RBC)-dense cores, and microdomains enriched in neutrophil extracellular traps (NETs), each presenting distinct molecular and mechanical signatures that can serve as sensing handles. We then analyze emerging stimulus-responsive nanoplatforms activated by thrombin, reactive oxygen species (ROS), shear, or pH, alongside biomimetic and flow-optimized targeting strategies designed to overcome washout and penetration barriers. Particular emphasis is placed on theranostic systems that integrate imaging and therapy, laying the foundation for feedback-guided intervention. To organize this rapidly evolving field, we propose Closed-Loop Readiness Levels (CLRL) as a translational framework that classifies thrombolytic technologies along a five-tier scale. The scale runs from open-loop systems with no feedback (CLRL-0) to fully autonomous, self-regulating nanosystems that adapt therapy in real time and terminate it once reperfusion is achieved (CLRL-4). Across experimental models, closed-loop concepts show promise in improving spatial precision, reducing systemic exposure, and adapting lytic intensity to clot resistance. However, key barriers remain, including hemodynamic complexity, protein corona effects, sensor specificity, and integration of reporting with autonomous control. Intermediate levels capture the progressive integration of stimulus-triggered activation, thrombus targeting, therapeutic actuation, and reporting before full autonomous control is reached. By unifying disparate advances under a control-systems paradigm, this review positions closed-loop thrombolysis as a transformative direction in stroke therapy, with the potential to shift treatment from static dosing toward responsive, intelligent, and patient-specific vascular intervention.</p> Graphical Abstract <p></p>